Neoadjuvant (pre-operative) treatment is both a clinical trial model to compare the efficacy of first-line treatments and a translational research model to identify biomarkers and imaging methods that predict or monitor treatment response. A central tenet of neoadjuvant clinical trials is that tumor response should be strongly prognostic for patient survival. At present there are several different classifications of pathologic response being used in neoadjuvant trials. These variably account for tumor size, cellularity of the tumor bed, cytologic changes, in situ disease, and nodal burden; and they have varying degrees of patient survival data to suggest clinical validity.
Pathologic complete response (pCR) has been adopted as the primary endpoint for trials of neoadjuvant treatment for breast cancer because it is associated with long-term survival, and yet the definition of pCR is still not uniform. While it is generally held that a definition of pCR should include patients without residual invasive carcinoma in the breast (pT0), the presence of nodal metastasis, minimal residual cellularity, and residual in situ carcinoma are not consistently defined as pCR or residual disease (RD). When pCR is defined as no residual invasive cancer in the breast, the number of involved regional lymph nodes is inversely related to survival. Conversely, patients who convert to node-negative status after treatment have excellent survival, even if there is residual disease in the breast. Alternatively, the Miller and Payne classification ignores tumor size and nodal status altogether, and estimates only the decrease in cancer cellularity after treatment. This was also related to survival in a report including 176 patients. Two other classifications (Sataloff and Chevallier) also assess the post-treatment histologic and cytologic changes, although there is limited follow-up data to compare with survival. Reduction in cancer cellularity is generally greater when the residual tumor is small, suggesting that both size and cellularity provide response information. These different classifications suggest that reduction in the primary tumor size, regional nodal burden, and cellularity of the tumor bed all contribute meaningful pathologic response information.
It is imperative that pathologic response be defined with greatest prognostic relevance in order to optimize the clinical and scientific information that can be gained from neoadjuvant clinical trials. Dichotomization of response as pCR or residual disease (RD) is overly simplistic for these objectives, particularly because residual disease (RD) after neoadjuvant treatment includes a broad range of actual responses from near-pCR to frank resistance and disease progression.